Synthesis And Qualitative And Quantitative Study On Crystal Form Of Tetracaine Hydrochloride

Local anesthetics have important application value in modern medical treatment.Tetracaine hydrochloride,as an ester local anesthetic,is mainly used for mucosal anesthesia.It has a rapid effect,little damage to mucosal epithelium and no influence on intraocular pressure and pupil.It has a unique advantage in the application of ophthalmic surface anesthesia.Improving the existing API process meets the requirements of green chemistry.However,it is of great value and significance to explore a better synthesis process of tetracaine hydrochloride.By consulting and analyzing the domestic and foreign literatures,it can be seen that the current synthesis route of tetracaine hydrochloride has the following shortcomings:high and rare raw materials,expensive catalysts,harsh reaction conditions,long reaction time,low yield,serious environmental pollution and so on.In addition,polymorphism and solvation are common in local anesthetics,but polymorphism of tetracaine hydrochloride needs to be further clarified.With the increasing demand for drug stability,clinical efficacy and safety at home and abroad,researchers began to pay more attention to the relationship between the existence of drug polymorphism and drug safety.Different crystal forms of the same drug may have significant differences in physical and chemical properties and clinical efficacy,so qualitative and quantitative analysis of drug crystal forms is indispensable in the development and production process of crystal drug products.In this paper,the synthesis process and crystal form qualitative and quantitative of tetracaine hydrochloride were studied,the main contents include:(1)Study on the synthesis of tetracaine hydrochlorideThe synthetic route obtained by exploration is as follows:tetracaine hydrochloride is obtained from benzocaine by N-alkylation,transesterification and salt formation.The optimum technological conditions for N-alkylation are as follows:using benzocaine and bromobutane as raw materials,organic base A as catalysts,acetonitrile as solvent,benzocaine:bromobutane:organic base A:acetonitrile=1:2:2:0.3,the reaction temperature was 120?,the reaction time was 3 h,the optimized yield was increased by 7.7%,and the time was shortened by 7 h.The optimum technological conditions for transesterification reaction are as follows:ethyl 4-(butylamino)benzoate and dimethylethanolamine are used as the raw material,ethyl 4-(butylamino)benzoate:dimethylethanolamine=1:1.5,the reaction temperature was 100?,the reaction time was 11h,dimethylethanolamine was added in batches.The yield was 71.4%,the optimized yield and purity have been improved.The preferred process for the salt formation reaction was:direct introduction of dry HCl gas into the tetracaine ethanol solution,tetracaine:ethanol=1:2,and the rate of HCl gas overflow was about 260/min.The calculated yield of ethyl 4-(butylamino)benzoate was 23.5%higher than the literature value.The total yield and purity of benzocaine were 53.3%and 99.2%(HPLC).In a word,by changing the reaction solvent and ratio,reactant feeding mode and catalyst,the yield of the new process was increased by 25.3%and the atomic utilization rate was greatly increased.(2)Qualitative and Quantitative Study on the Crystal Form of Tetracaine HydrochlorideThe form A of tetracaine hydrochloride was prepared by cooling crystallization method,and the form B was prepared by base formation.The qualitative analysis was carried out by Differential Scanning Calorimetry(DSC),Powder X-ray Diffraction(PXRD),Infrared Spectrum(IR),Raman(RM)and Electron Microscope(SEM).The melting point of form A is 150?,the melting point of form B is 140?.At room temperature,form B is a thermodynamically stable product.At 100-120?,form A is a thermodynamically stable product,and the two are interconverting systems.Analysis of different detection techniques found that the DSC method was beneficial to the quantitative analysis of form A and form B,and the endothermic peaks of the two crystal forms differ by 10?.Based on the linear relationship between the quality of the crystal form A and the form B,and the linear relationship between the crystal content and the endothermic peak enthalpy value,a standard curve was drawn by formulating different content of mixed crystal samples.The regression equation of internal crystal form A is y=0.899x+0.192,R~2=0.9937,and the regression equation of crystal form B is y=0.331x+21.328,R~2=0.9991.The results show that the linear relationship is good.The solubility of tetracaine hydrochloride was investigated by the balance method.The solubility data of tetracaine hydrochloride were fitted by suitable equation model,and the fitted results were in good agreement with the experimental data.The enthalpy and entropy of dissolution of tetracaine hydrochloride were estimated based on regression of the solubility data by using the van?t Hoff equation,and the dissolving process was endothermic and entropy-driving,which is the guiding significance for the crystallization process and refining of tetracaine hydrochloride.